Low-density lipoprotein (LDL) particles are the major carriers of cholesterol in the circulating blood. A fraction of the circulating LDL particles cross the arterial endothelium and carry cholesterol into the innermost layer of the arterial wall, the intima. In this subendothelial space, modification of low density lipoprotein (LDL) particles and their interaction with the molecules of the extracellular matrix and foam cell formation are two key processes determining the development of the atherosclerotic lesions. Our research group is interested in examining these processes. We have recently focused on lipoprotein aggregation and determined the mechanisms of LDL aggregation. We have also reported how LDL modification modifies the binding of LDL to the components of the arterial wall, and analyzed the effect of extracellular conditions on modification and retention of LDL. Moreover, we have discovered that acidic extracellular pH, such as found in atherosclerotic lesions, renders LDL particles particularly susceptible for modifications by proteases and lipases, and induces formation of extremely large LDL aggregates. Such macro-aggregates remain stuck in the intima, and thus are unable to return to the circulating blood. We have also found that acidic pH enhances the interactions between LDL and extracellular matrix, another element blocking return of LDL back to circulation.
Most recently, we discovered that some individuals have in their circulation LDL particles that are exceptionally prone to aggregation, and identified this property of LDL as a novel risk factor for atherosclerotic cardiovascular disease in humans. The aggregation-prone LDL particles are rich in sphingolipids, a lipid class often associated with inflammatory conditions, such as atherosclerosis. We are continuing these studies by using both experimental animals and human samples collected in biobanks. We have also determined the effects of the modified LDL particles on cells relevant for atherogenesis. The cellular effects of modified and aggregated LDL are likely to be important in explaining the inflammatory response to modified LDL in atherosclerosis. Importantly, in humans, the inter-individual differences in LDL modification and aggregation may partly explain the person-to-person variation in the susceptibility to the development of atherosclerosis and its atherothrombotic clinical complications, such as myocardial infarction. Currently we examine the detailed mechanisms of LDL aggregation with the aim of understanding how to inhibit LDL modification and ensuing particle aggregation. If we succeed in this endeavor, then we may be in a better position to prevent cholesterol accumulation and inflammation in the arterial wall.
The second line of research in our laboratory: focus on the role of mast cells in atherogenesis
Mast cells are potent actors involved in inflammatory reactions in various tissues, including the intimal layer of atherosclerotic arteries. In the arterial intima, the site of atherogenesis, mast cells are activated to degranulate, and thereby triggered to release an abundance of preformed inflammatory mediators, notably histamine, heparin, neutral proteases and cytokines stored in their cytoplasmic secretory granules. By degrading apolipoprotein B-100, the main apolipoprotein component of LDL, mast cell-derived proteases may render LDL more proatherogenic, and by degrading apolipoprotein A-I, the main apolipoprotein component of high-density lipoprotein (HDL), the proteases may impede the anti-atherogenic functions HDL. The activated mast cells may also adversely alter the functions of different types of cells present in atherosclerotic lesions, and, furthermore, they may impede the structural integrity of the intimal extracellular matrix. Together, the multitude of extracellular and cellular actions of mast cells in the arterial wall has the potential to contribute to the initiation and progression of atherosclerosis, and ultimately also to destabilization and rupture of advanced atherosclerotic plaques with ensuing atherothrombotic complications. Direct extrapolation to the clinic needs to be cautious, however. But, if the concept of mast cell-dependent plaque destabilization can be confirmed in human studies, attenuation of mast cell activity in atherosclerotic lesions by mast cell-stabilizing drugs could offer a new therapeutic opportunity for patients at risk for acute coronary syndromes.